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MLK4 has negative effect on TLR4 signaling

Cellular & Molecular Immunology volume 9, pages 27–33 (2012)Cite this article

Abstract

The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosis factor-α (TNF-α). The TNF production is mediated by a series of signaling events and subsequent transcriptional and post-transcriptional activation of the TNF gene. Termination of TLR-mediated cellular signaling is also important for a proper immunoresponse, since sustained cytokine expression can result in immune disorders. Here we identified that mixed-lineage kinase (MLK) 4 is a TLR4-interacting protein. Unlike previously characterized MLK group members, MLK4 cannot act as a mitogen-activated protein kinase kinase kinase (MAP3K) to mediate c-Jun N-terminal kinase (JNK), p38 or extracellular signal-regulated kinase (ERK) activation. Rather, MLK4 appears to be able to inhibit lipopolysaccharide (LPS)-induced activation of the JNK or ERK pathways, but does not have effect on LPS-induced p38 or NF-κB activation. The LPS-induced TNF production in MLK4 knockdown and overexpression cells were also increased and reduced, respectively. These data demonstrate that MLK4 is a negative regulator of TLR4 signaling.

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Acknowledgements

This work was supported by grants from NSF China (30830092, 30921005, 91029304 and 81061160512), 973 Program (2009CB522200) and National Institutes of Health (AI41637 and AI68896).

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Author notes

  1. Alim Seit-Nebi and Wei Cheng: The authors contributed equally to this work.

  2. Dr J Hua, The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China. E-mail: jhan@xmu.edu.cn

Authors and Affiliations

  1. The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China

    Alim Seit-Nebi, Wei Cheng, Hong Xu & Jiahuai Han

  2. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, USA, CA

    Alim Seit-Nebi

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  1. Alim Seit-Nebi
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  4. Jiahuai Han
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Seit-Nebi, A., Cheng, W., Xu, H. et al. MLK4 has negative effect on TLR4 signaling. Cell Mol Immunol 9, 27–33 (2012). https://doi.org/10.1038/cmi.2011.15

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